The family of fibroblast growth factor receptor (FGFR) is composed of four members (FGFR1, FGFR2, FGFR3 and FGFR4), which belong to the kinase of the receptor tyrosine kinases family. FGF binding results in dimerization of FGFR, followed by autophosphorylation of the receptors and activation of downstream signal pathways. Receptor activation is sufficient for the recovery and activation of specific downstream signal partners involved in the regulation of diversification processes such as cell growth, cell metabolism and cell survival. Thus, FGF/FGFR signal pathway has a multi-effect in many key biological processes such as tumor cell proliferation, migration, infiltration, angiogenesis.
In recent years, there have been a growing number of evidences showing that the mutations in the amplifications of FGFR1, FGFR2, FGFR3 and FGFR4 genes are present in various types of cancers. A large number of evidences show that: there are mutations of FGFR1 genes in breast cancer, non-small cell lung cancer, small cell lung cancer and glioblastoma, formation of fusion proteins caused by the gene transposition of FGFR1 in acute myeloid leukemia, over-expression of FGFR1 in pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer; there is a phenomenon of gene mutation and amplification of the FGFR2 genes in gastric cancer, breast cancer and uterine cancer, while over-expression of FGFR2 in prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, brain tumor, colorectal cancer; there are mutations of FGFR3 genes in multiple myeloma and bladder cancer, over-expression of FGFR3 in ovarian cancer, small cell lung cancer, non-small cell lung cancer, hepatocellular carcinoma; there are mutations of FGFR4 in lung cancer, ovarian cancer, prostate cancer and liver cancer etc., over-expression of FGFR4 in thyroid cancer, ovarian cancer.
At present, a series of FGFR inhibitor patents have been disclosed, including WO2006000420, WO2008075068 and WO2010129509 etc., the drugs that are currently in clinical phase II are LY-2874455, AZD-4547 and BGJ-398 etc., the drugs in clinical phase I are Debio-1347 and so on. But these studies for antitumor are far from enough, and it is still necessary to study and develop new FGFR inhibitors.